2-189003469-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000090.4(COL3A1):c.2607+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.91

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-189003469-G-T is Pathogenic according to our data. Variant chr2-189003469-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101149.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.2607+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.2607+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.2508+5G>T		splice_donor_5th_base_variant, intron_variant		1
COL3A1	ENST00000467886.1	n.42+5G>T		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2022

Identified in a patient with vEDS in published literature (Wu et al., 1993); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate exon skipping and loss of exon 37 (Wu et al., 1993); In silico analysis supports a deleterious effect on splicing; Damages or destroys the splice donor site in intron 37, and is expected to cause abnormal gene splicing; as the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25525159, 9399899, 8477261) -

Ehlers-Danlos syndrome, type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Collagen Diagnostic Laboratory, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779457; hg19: chr2-189868195;